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proprotein convertase subtilisin/kexin type 9; neural apoptosis-regulated convertase 1; NARC-1; Proprotein convertase 9; PC9; subtilisin/kexin-like protease PC9 (PCSK9 NARC1 PSEC0052)

Function: - protease with charge-relay system - role in differentiation of cortical neurons - may play a role in cholesterol homeostasis - binds to LDL receptors, increasing the degradation of LDL receptors & reducing clearance of LDL cholesterol from the circulation [3] - the soluble zymogen undergoes autocatalytic intramolecular processing in the endoplasmic reticulum, resulting in cleavage of its propeptide that remains associated with the secreted enzyme - the precursor protein but not the mature protein may form multimers Inhibition: - inhibited by EGTA Cofactor: Ca+2 (probable) Structure: - belongs to the peptidase S8 family - contains 1 peptidase S8 domain Compartment: secreted Alternative splicing: named isoforms=2 Expression: - highly expressed in liver - expressed in neuroepithelioma, colon carcinoma, hepatic & pancreatic cell lines, & in Schwann cells Pathology: - mutations associated with autosomal dominant hypercholesterolemia 3 Polymorphism: - variant Leu-23 ins polymorphism in PCSK9 may modify effect of LDLR mutation in familial hypercholesterolemia - some PCSK9 variants decrease serum of LDL cholesterol [5] Pharmacology: - PCSK9 inhibitors (monoclonal antibodies, i.e. alirocumab, evolocumab ..) increase recycling of LDL receptors & reduce LDL cholesterol levels [3] Comparative biology: - CRISPR knock out of the PCSK9 gene in the livers of mice increases LDL receptors & reduces plasma LDL cholesterol without observable adverse effects [4]

Related

autosomal dominant hypercholesterolemia 3 PCSK9 gene mutation

General

glycoprotein phosphoprotein protease; proteinase; endopeptidase secreted protein

Properties

SIZE: entity length = 692 aa MW = 74 kD COMPARTMENT: extracellular compartment MOTIF: signal sequence {1-30} Ser phosphorylation site {S47} proteolytic site {152-153} Peptidase S8 {161-431} MOTIF: aspartate residue {D186} cysteine residue {C223} MODIFICATION: cysteine residue {C255} histidine residue {H226} cysteine residue {C255} MODIFICATION: cysteine residue {C223} cysteine residue {C323} MODIFICATION: cysteine residue {C358} cysteine residue {C358} MODIFICATION: cysteine residue {C323} serine residue {S386} N-glycosylation site {N533} Ser phosphorylation site {S688}

Database Correlations

OMIM correlations MORBIDMAP 607786 UniProt Q8NBP7 PFAM correlations Entrez Gene 255738 Kegg hsa:255738

References

  1. UniProt :accession Q8NBP7
  2. SeattleSNPs http://pga.gs.washington.edu/data/pcsk9/
  3. Roth EM et al Atorvastatin with or without an Antibody to PCSK9 in Primary Hypercholesterolemia. N Engl J Med. Oct 31, 2012 PMID: 23113833 http://www.nejm.org/doi/full/10.1056/NEJMoa1201832 - Giugliano RP et al Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 in combination with a statin in patients with hypercholesterolaemia (LAPLACE-TIMI 57): a randomised, placebo-controlled, dose-ranging, phase 2 study The Lancet, Early Online Publication, 6 November 2012 PMID: 23141813 http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(12)61770-X/abstract - Koren MJ et al Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 as monotherapy in patients with hypercholesterolaemia (MENDEL): a randomised, double-blind, placebo-controlled, phase 2 study The Lancet, Early Online Publication, 6 November 2012 PMID: 23141812 http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(12)61771-1/abstract - Tonkin AM and Watts GF Into the future: diversifying lipid management The Lancet, Early Online Publication, 6 November 2012 PMID: 23141810 http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(12)61888-1/fulltext
  4. Ding Q et al Permanent alteration of PCSK9 with in vivo CRISPR-Cas9 genome editing. Circ Res 2014 Jun 10 PMID: 24916110 http://circres.ahajournals.org/content/early/2014/06/10/CIRCRESAHA.115.304351
  5. Ference BA, Robinson JG, Brook RD et al. Variation in PCSK9 and HMGCR and risk of cardiovascular disease and diabetes. N Engl J Med 2016 Dec 1; 375:2144 PMID: 27959767 http://www.nejm.org/doi/10.1056/NEJMoa1604304